Abstract
Chronic low-grade inflammation, adipocyte hypertrophy, and glucose intolerance are common features of obesity and a risk factor for cancer. Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is an adaptor protein that also possesses a non-conventional E3 ubiquitin ligase activity. In response to receptor-mediated events, TRAF6 activates transforming growth factor-activated kinase 1 (TAK1), which leads to activation of the MAPK and nuclear factor-kappa B (NF-κB) signaling pathways. However, the roles of TRAF6 and TAK1 in the regulation of adipocyte function remain less understood. Here, we demonstrate that adipocyte-specific deletion of TAK1, but not TRAF6, in mice reduces the survival of adipocytes and abundance of white adipose tissue (WAT). Adipocyte-specific ablation of TAK1, but not TRAF6, increases the expression for markers of beige/brown fat in WAT. Deletion of TAK1 in WAT increases phosphorylation of AMPK, abundance of PGC-1α, non-canonical NF-κB signaling, markers of M2 macrophages, and diminishes phosphorylation of JNK and canonical NF-κB signaling. Levels of TRAF6 and enzymatic activity of TAK1 are increased in WAT of mice fed with high-fat diet (HFD). Our results demonstrate that ablation of TAK1 drastically reduces HFD-induced obesity and improves energy expenditure and glucose metabolism. In contrast, adipocyte-specific ablation of TRAF6 has a minimal effect on HFD-induced obesity. Collectively, our results suggest that even though TRAF6 is an upstream activator of TAK1 in many signaling cascades, inactivation of TAK1, but not TRAF6, regulates adipocyte survival, energy expenditure, and HFD-induced obesity in mice.
Highlights
Obesity is a health care crisis of global pandemic status that is caused by a chronic imbalance between energy intake and expenditure [1]
While adipocytespecific deletion of transforming growth factor-activated kinase 1 (TAK1) did not affect wet weight of liver (Figure 1G), we found a small but significant decrease in wet weight of gastrocnemius (GA) and tibialis anterior (TA) muscles of aTAK1-KO mice compared with their WT littermates (Figure 1H)
Levels of TAK1 were significantly reduced in both white adipose tissue (WAT) and brown adipose tissue (BAT) of aTAK1KO mice compared with their controls (Figure 1K, 1L)
Summary
Obesity is a health care crisis of global pandemic status that is caused by a chronic imbalance between energy intake and expenditure [1]. Adipose tissue is broadly classified as either white adipose tissue (WAT) or brown adipose tissue (BAT). WAT is the major energy storage depot characterized by large lipid droplets and is a prominent endocrine organ, producing hormones that regulate feeding and satiety [3]. BAT is an energy dissipation depot characterized by numerous mitochondria and high levels of expression of uncoupling protein-1 (UCP1). Like BAT, beige adipocytes express high levels of UCP1 and have a high energy expenditure capacity [3, 4]. It is evident that increasing the abundance of beige adipocytes is an approach that could prevent and treat obesity and T2D [8]. The signaling mechanisms that regulate the acquisition of beige properties by WAT remain poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
